Norepinephrine dopamine

Monoamine Oxidase Inhibitors. MAOIs inactivate the enzyme MAO, which is responsible for the oxidative deamination of a variety of endogenous and exogenous substances. Among the endogenous substances are the neurotransmitters, norepinephrine, dopamine, and serotonin. The prototype MAOI is iproniazid [54-92-2] (25), originally tested as an antitubercular dmg and a close chemical relative of the effective antitubercular, isoniazid [54-85-3] (26). Tubercular patients exhibited mood elevation, although no reHef of their tuberculosis, following chronic administration of iproniazid. In... 

The COMT inhibitors should not be administered with the monoamine oxidase (MAO) inhibitors (see Chap. 31) because there is an increased risk of toxicity. If the COMT inhibitors are administered with norepinephrine, dopamine, dobutamine, methyldopa, or epinephrine, there is a risk of increased heart rate, arrhythmias, and excessive blood pressure changes. 

Povlock, SL and Amara, SG (1997) The structure and function of norepinephrine, dopamine and serotonin transporters. In Neurotransmitter Transporters Structure, Function, and Regulation (Ed. Reith, MEA), Humana Press, Totowa, NJ, pp. 1-28. 

Weiss, JM, Goodman, PA, Lostito, BG, Corrigan, S, Charry, JM and Bailey, WH (1981) Behavioral depression produced by an uncontrollable stressor relationship to norepinephrine, dopamine and serotonin levels in various regions of rat brain. Brain Res. Rev. 3 167-205. 

Different types of antidepressants are supposed to work by different means. SSRIs (selective serotonin reuptake inhibitors) are supposed to increase serotonin levels. NDRIs (norepinephrine dopamine reuptake inhibitors) are supposed to increase norepinephrine and dopamine, rather than serotonin. These two types of antidepressants are supposed to be selective , affecting the... 

For neurons that synthesize epinephrine or norepinephrine, dopamine P-hydroxylase is the next step in the biosynthetic pathway 213... 

There is evidence for the contribution of serotonin dysfunction to mania, and in the mechanism of action of mood stabilizers [19], however, specific data on the serotonergic system and mania are fewer and variable. Moreover, altered functioning of other neurotransmitters in mania such as norepinephrine, dopamine, acetylcholine, and GABA, and their interaction with serotonin, are also likely to be involved in the pathogenesis of mood disorders. Differences in these neurotransmitter systems possibly underlie differences in the pathogenesis of depressive and manic episodes. 

Sixteen years later, when the first edition of Basic Neurochemistry appeared, Sol Snyder s chapter could classify norepinephrine, dopamine and serotonin as... 

Numerous reports of altered neurotransmitter and hormone functions which have been associated with the affective disorders are reviewed by Levell [142]. It was originally proposed that one or more of the neurotransmitter amines in the brain (norepinephrine, dopamine, serotonin) may be functionally elevated in manic patients and reduced in depressed patients [143]. For instance, an increase in the production of dopamine, observed in a number of case reports, is thought to be the cause of the switch into the manic phase in bipolar patients. For example, Bunney et al. reported an increase in the level of homovanillic acid (HVA), a... 

The effect of non-participating ligands on the copper catalyzed autoxidation of cysteine was studied in the presence of glycylglycine-phosphate and catecholamines, (2-R-)H2C, (epinephrine, R = CH(OH)-CH2-NHCH3 norepinephrine, R = CH(OH)-CH2-NH2 dopamine, R = CH2-CH2-NH2 dopa, R = CH2-CH(COOH)-NH2) by Hanaki and co-workers (68,69). Typically, these reactions followed Michaelis-Menten kinetics and the autoxidation rate displayed a bell-shaped curve as a function of pH. The catecholamines had no kinetic effects under anaerobic conditions, but catalyzed the autoxidation of cysteine in the following order of efficiency epinephrine = norepinephrine > dopamine > dopa. The concentration and pH dependencies of the reaction rate were interpreted by assuming that the redox active species is the [L Cun(RS-)] ternary complex which is formed in a very fast reaction between CunL and cysteine. Thus, the autoxidation occurs at maximum rate when the conditions are optimal for the formation of this species. At relatively low pH, the ternary complex does not form in sufficient concentration. 

The first step is catalysed by the tetrahydrobiopterin-dependent enzyme tyrosine hydroxylase (tyrosine 3-monooxygenase), which is regulated by end-product feedback is the rate controlling step in this pathway. A second hydroxylation reaction, that of dopamine to noradrenaline (norepinephrine) (dopamine [3 oxygenase) requires ascorbate (vitamin C). The final reaction is the conversion of noradrenaline (norepinephrine) to adrenaline (epinephrine). This is a methylation step catalysed by phenylethanolamine-jV-methyl transferase (PNMT) in which S-adenosylmethionine (SAM) acts as the methyl group donor. Contrast this with catechol-O-methyl transferase (COMT) which takes part in catecholamine degradation (Section 4.6). 

Traditionally, most affective disorders have been treated with compounds that resemble the neurotransmitters that are deficient or in excess in specific brain regions. The aberrant levels of neurotransmitters (or their receptors), such as norepinephrine, dopamine, acetylcholine, and serotonin, have correlated with behavioral symptoms of schizophrenia, depression, anxiety, sleep disorders, motor dysfunctions, attention difficulties, and cognitive disorders. Most drugs discovered for these disorders resulted from screening compounds directly in rodent behavioral models that mimic the behavior of the disease. In these cases, the molecular target" or mechanism of action was assumed to be the deficiency or excess of a neurotransmitter. 

Lakshmana MK, Trichur TR. 1997. An isocratic assay for norepinephrine, dopamine and 5-hydroxytryptamine using their native fluorescence by high-performance liquid chromatography with fluorescence detection in discrete brain areas of rat. Anal Biochem 246 166-170. 

Stolerman IP, Chamberlain S, Bizarro L, Fernandes C, Schalkwyk L (2004) The role of nicotinic receptor alpha7 subunits in nicotine discrimination. Neuropharmacology 46 363-371 Summers KL, Giacobini E (1995) Effects of local and repeated systemic administration of (—) nicotine on extracellular levels of acetylcholine, norepinephrine, dopamine, and serotonin in rat cortex. Neurochem Res 20 753-759... 

The two pioneer drugs for schizophrenia are chlorpromazine and reserpine. Reserpine is known to reduce the brain levels of norepinephrine, dopamine, and serotonin. Since reserpine is also effective in coping with some of the symptoms of schizophrenia, perhaps an abnormally high concentration of one or more of these monoamines is a contributing factor to this disorder. 

Listing of antidepressants grouped by principal mechanism of action in the synapse. Abbreviations MAOI—irreversible = irreversible monoamine oxidase inhibitor MAOI—reversible = reversible monoamine oxidase inhibitor NDRl = norepinephrine/ dopamine reuptake inhibitor NRI = norepinephrine reuptake inhibitor NSRl = norepinephrine/serotonin reuptake inhibitor NSSA = norepinephrine/specific serotonin agonist SRI = serotonin reuptake inhibitor SRl/serotonin-2 blocker = serotonin reuptake inhibitor and serotonin-2 receptor antagonist. 

Monoamine Oxidase Inhibitors (MAOIs). The MAOls work in a unique fashion by blocking the activity of an enzyme that degrades each of three key brain transmitters norepinephrine, dopamine, and serotonin. These widespread effects on several brain transmitter systems make the MAOls a potentially very effective class of medications for a variety of disorders. A few small studies have evaluated the usefulness of the MAOls in the treatment of BPD and found them moderately helpful for the impulsivity associated with this illness. Unfortunately, the requirements for strict dietary restrictions due to a risk of hypertensive crisis severely limit the usefulness of MAOls in the treatment of BPD. These restrictions are a particular concern when treating patients who have problems with impulsivity and are therefore likely to have difficulty maintaining the dietary regimen. For this reason, although they may theoretically be helpful, MAOls should only be used to treat BPD after other more easily tolerated medications have been tried and have failed. In the near future, so-called reversible MAOls that appear to avoid the need for diet restrictions may become available. If so, this will allow us to reconsider their use in the treatment of BPD. For more information regarding the use of MAOls, please refer to Chapter 3. 

As we move forward with our discussion, we ll devote a section of this chapter to each of the key neurotransmitter systems that psychotropic medications interact with. We will discuss the following systems norepinephrine, dopamine, serotonin, GABA, acetylcholine, and histamine. Within each of the sections is a description of the effects that can be anticipated when a medication enhances the activity of that transmitter (reuptake inhibitors or agonists), and the effects to expect when a medication interferes (receptor antagonists) with the activity of that same transmitter. We will then describe strategies that can be implemented to help minimize and/or manage these side effects. 

Figure 7.3. Structural formulae of the noradrenaline (norepinephrine)/dopamine reuptake inhibitor amfebutamone (bupropion) and some nonselective noradrenaline and serotonin (5-hydroxytr3 tamine 5-HT) reuptake inhibitors (venlafaxine, and...

Conventionally called adrenergic neuron blockers, the last group of adrenoblockers are drugs that suppress synthesis, storage, and release of biogenic amines (norepinephrine, dopamine, or serotonin) in nerve endings. 

Adrenergic neuron blockers cause degradation of biogenic amines in neuron endings. These drugs can interfere with the synthesis, storage and release of norepinephrine, dopamine, and serotonin. 

Reserpine causes a breakdown of norepinephrine, dopamine, and serotonin in neuron endings. It weakens intracellular uptake of biogenic amines and reduces the ability if storing them in vesicles. It is possible that reserpine acts on membrane vesicles, irreversibly inhibiting ATP-Mg (adenosinetriphosphate) requiring process that is responsible for the uptake of biogenic amines in intemeuronal vesicles. Breakdown of catecholamines is expressed by a decreased number of intraneuronal serotonin and dopamine. 

There are more than 10 billion neurons that make up the human nervous system, and they interact with one another through neurotransmitters. Acetylcholine, a number of biogenic amines (norepinephrine, dopamine, serotonin, and in all likelihood, histamine and norepinephrine), certain amino acids and peptides, and adenosine are neurotransmitters in the central nervous system. Amino acid neurotransmitters are glutamic and aspartic acids that excite postsynaptic membrane receptors of several neurons as well as y-aminobutyric acid (GABA) and glycine, which are inhibitory neurotransmitters. Endorphins, enkephalins, and substance P are considered peptidergic transmitters. There are many compounds that imitate the action of these neurotransmitters. 

Reserpine canses release of norepinephrine, dopamine, and serotonin at nenronal termini. It weakens the intracellnlar uptake of biogenic amines and decreases the ability to store them in vesicles. 

Admixture incompatibilities - Avoid adding sodium bicarbonate to parenteral solutions containing calcium, except where compatibility is established precipitation or haze may result. Norepinephrine, dopamine, and dobutamine are incompatible. 

Drugs metabolized by COMT Administer drugs known to be metabolized by COMT (ie, isoproterenol, epinephrine, norepinephrine, dopamine, dobutamine, methyidopa, apomorphine, isoetherine, bitolterol) with caution in patients receiving entacapone regardless of the route of administration (including inhalation), as their interaction may result in increased heart rates, arrhythmias, and excessive changes in blood pressure. 

Isogawa K, Akiyoshi J, Hikichi T, Yamamoto Y, Tsutsumi T, Nagayama H (2000) Effect of corticotropin releasing factor receptor 1 antagonist on extracellular norepinephrine, dopamine and serotonin in hippocampus and prefrontal cortex of rats in vivo. Neuropeptides 34 234-239... 

Since the enzyme that converts dopamine to norepinephrine (dopamine (3-hydroxylase) is located only within the vesicles, the transport of dopamine into the vesicle is an essential step in the synthesis of norepinephrine. This same transport system is essential for the storage of norepinephrine. There is a tendency for norepinephrine to leak from the vesicles into the cytosol. If norepinephrine remains in the cytosol, much of it will be destroyed by a mitochondrial enzyme, monoamine oxidase MAO). However, most of the norepinephrine that leaks out of the vesicle is rapidly returned to the storage vesicles by the same transport system that carries dopamine into the storage vesicles. It is important for a proper understanding of drug action to remember that this single transport system, called vesicular transport, is an essential element of both synthesis and storage of norepinephrine. 

Reserpine also interferes with the neuronal storage of a variety of central transmitter amines such that significant depletion of norepinephrine, dopamine, and 5-hydroxytryptamine (serotonin) occurs. This central transmitter depletion is responsible for the sedation and other CNS side effects associated with reserpine therapy. The depletion of brain amines also may contribute to the antihypertensive effects of reserpine. 

Norepinephrine > dopamine presy-naptic reuptake blockade... 

The enzyme MAO metabolizes some of the neurotransmitters affected by some drugs of abuse, namely epinephrine, norepinephrine, dopamine, and serotonin. Dangerously high levels can result if an inhibitor of this enzyme, or monoamine oxidase inhibitor (MAOI), is used along with the drug of abuse. 

Pharmacologic targeting of monoamine transporters. Commonly used drugs such as antidepressants, amphetamines, and cocaine target monoamine (norepinephrine, dopamine and serotonin) transporters with different potencies. A shows the mechanism of reuptake of norepinephrine (NE) back into the noradrenergic neuron via the norepinephrine transporter (NET), where a proportion is sequestered in presynaptic vesicles through the vesicular monoamine transporter (VMAT). and C show the effects of amphetamine and cocaine on these pathways. See text for details. 

Many inhibitors of the amine transporters for norepinephrine, dopamine, and serotonin are used clinically. Although specificity is not absolute, some are highly selective for one of the transporters. Many antidepressants, particularly the older tricyclic antidepressants can inhibit norepinephrine and serotonin reuptake to different degrees. This may lead to orthostatic tachycardia as a side effect. Some antidepressants of this class, particularly imipramine, can induce orthostatic hypotension presumably by their clonidine-like effect or by blocking 04 receptors, but the mechanism remains unclear. 

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